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Monday, June 23, 2008

[Update: Well, it looks like Lilly will have to wait on the champagne, at least for now. FDA extended the review of prasugrel by three months after receiving "supplemental information" during the review. "We will continue to work closely with the FDA throughout the review process and continue discussions to determine if any requirements under the new FDA Amendments Act (FDAAA) will apply," Lilly VP-global regulatory affairs Jennifer Stotka said in a statement. To read the full release, click here.]

There’s nothing like a ticking clock as a deadline approaches to ratchet up the drama behind an FDA decision. Remember Provenge? On June 26, or possibly before then, Eli Lilly will find out whether its novel blood thinner prasugrel (Effient) will be granted approval, delayed or rejected.

We think Lilly may want to get the champagne ready. Here’s why:

1) The Data: When it comes to FDA approvals, it’s all about the data. No question. In Lilly’s Phase III 13,000-patient TRITON clinical study, prasugrel produced a 19% reduction in the composite primary endpoint of cardiovascular death, non-fatal heart attacks or non-fatal strokes when compared with clopidogrel (Plavix). By any standard, that’s a compelling result.

There’s been a lot of finger pointing regarding a more cautious FDA when it comes to new drug approvals and we’re not going to dismiss that here. However, sometimes the cases used as evidence to make that argument were for drugs that missed their primary endpoints or made it by the skin of their teeth and had important safety questions.

Those expecting an FDA decision to delay the application point to the statistically significant 32% increase in minor and major bleeding. That’s a strong point against approval in today’s regulatory environment. But when you consider the primary endpoint, those bleeds didn’t lead to deaths, heart attacks or strokes. To read more about our coverage of prasugrel, click here.

2) Priority Review: We think a lot of the hard work on prasugrel was done prior to the priority review designation. Here is what FDA says warrants that designation:

“A priority reviewdesignation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists....The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment.Such advances can be demonstrated by, for example:

a) evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;

b) elimination or substantial reduction of a treatment-limiting drug reaction;

c) documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or

d) evidence of safety and effectiveness in a new subpopulation, such as children.

Designation of a drug as “priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.”

FDA Office of New Drugs director John Jenkins is one of the most vocal advocates of the value linked to getting a priority review. He often cites the designation as the most telltale sign that a drug will receive a positive, first-cycle decision. It may be a leap, but we doubt such a high-profile drug in a treatment area with an established gold standard would have received a priority review without FDA having a strong idea of what they were going to do with it.

3) The (absence of an) Advisory Committee: This is another positive sign for Lilly, in our opinion. Why? Read this quote from former FDA drug center Steve Galson at a 2006 Stanford Research Group meeting in Washington:

“If it’s clear that the drug is very advantageous and helpful [then an advisory committee may not be necessary]…we’re just wasting everyone’s time because it’s obvious that this drug has to get on the market. On the contrary, if there’s some major drug safety issue that we know there isn’t any real disagreement...then we also don’t want to waste everyone’s time at a whole meeting.”

We think the former is the case with prasugrel when you pair it with the priority review. For example, if you look at Bayer/Onyx’ and Pfizer’s renal cell carcinoma drugs sorafenib (Nexavar)and sutinib (Sutent), respectively, both were priority reviews that resulted in timely approval without advisory committees. Both were viewed as significant advances in renal cell carcinoma therapy, an area that had been bereft of new treatments for years.

4) Sending a Message: Approving prasugrel by the PDUFA deadline would send a strong message to FDA stakeholders that the agency is willing to approve innovative drugs—that carry a pre-determined risk—in a timely fashion if the treatments demonstrate a real benefit to patients. Prasugrel appears to fall in that category. Moreover, a swift approval that meets the user fee deadline would allay many concerns over an FDA memo allowing reviewers to extend deadlines. To read more, click here.

5) Nissen Says Thumbs Up: Controversial Cleveland Clinic cardiologist Steve Nissen has been on record as saying prasugrel is “a good drug that should get approved.” Need we say more?

6) Bad Cordaptive Comparison: Drug company executives, the investment community, and FDA watchers highlight FDA’s decision to delay/kill Merck’s combo cholesterol drug niacin/laropiprant (Cordaptive) with a “non-approvable” letter in late April as a sign that prasugrel could get disappointing news. This is an apple and oranges comparison. Cordaptive was a standard review application in an area, cholesterol therapy, with an extensive number of effective treatments. Moreover, there appeared to be questions over the long-term risks of the anti-flushing agent laropiprant. When FDA reviews combo drugs there must be evidence that each component of the combination product makes a substantial contribution to the safety and/or efficacy of the combination product. In other words, the combination product has to be shown to be more safe and/or effective than either product alone. Clearly, FDA didn’t feel that was the case with Cordaptive.

Two key questions that will impact the decision and whether it will be made by June 26 are: 1) Who made the priority review decision?; and 2) Will prasugrel require an onerous REMS (risk evaluation and mitigation strategies) postmarket surveillance program?

If an office-level director, or Jenkins himself, signed off on the priority review, that bodes better for prasugrel’s chances of approval. It diminishes the chances of an intervention from a higher-ranking official to delay the decision.

We asked FDA who actually decides whether a drug is granted a priority review. Here’s what an FDA spokesperson says: “The decision on priority review designation is made by the OND division director based on a recommendation from the review team and based on the CDER standard as articulated in our guidance.”

The division director in this case is Norman Stockbridge, who reports into Office of Drug Evaluation I director Robert Temple.

As the decision relates to risk management, if a burdensome REMS program is required to monitor the bleeding risk, it could take a few extra months to work out the details.

In the end, based on the tea leaves, that FDA will approve prasugrel with a warning (not black-box) on bleeds and a REMS program that includes a prescribing MedGuide for patients, a physician education program and a postmarket study.

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